Maternal factors - pregnancy, calcium homeostasis and
implications for development

Maternal viral infection during pregnancy has been
hypothesised to alter fetal brain development indirectly - maternal
inflammatory response was shown in vitro to interfere in neuronal
development and CNS organisation [2273013,
12666123,
17029701]
(also see Immunity/Inflammation
for elevation in cytokine levels during pregnancy). In additon
to cytokines and other inflammatory mediators, maternal antibodies
have been suggested to play a possible role in some forms of
neurodevelopmental disorders, as the mice injected with serum
containing maternal brain antibodies exibited changes in fields
of exploration and motor coordination [12666123].

Another
study found that prenatal exposure to antibodies from mothers
of children with autism (MCAD) also produced neurobehavioral
alterations in mice - displayed anxiety-like behavior on and
had a greater magnitude of startle following acoustic stimulation.
On a social interaction paradigm, adult mice had alterations
of sociability. Pilot studies of immune markers in MCAD IgG-exposed
embryonic brains suggest evidence of cytokine and glial activation.
These studies demonstrate that the transplacental passage of
IgG from MCAD is capable of inducing long-term behavioral consequences
[19362378].

The role
of antibodies to several neuronal and muscle ion channels
in the etiology of neuromuscular transmission disorders is well
known. For example the ability of anti-tissue antibodies to
cause contraction of smooth muscle cells is thought to be due
to their interaction and modulation of with plasma membrane
calcium channels, with the most likely involvement of LTCC
[8288445].

Congenital Heart Block (CHB) is a congenital heart condition
caused by maternal autoantibody-mediated disturbance of LTCC
in the heart of the newborn - maternal antibodies recognize
human LTCC alpha(1C)-protein and functionally inhibit the expressed
current. It should be noted that mothers of affected children
frequently suffer autoimmune diseases, and that the fetal heart
appears to be uniquely vulnerable and that the mother's heart
is almost never affected with complete heart block despite exposure
to identical circulating levels of autoantibodies [11427485].

As voltage-gated ion channels are expressed in the brain as
well as at the neuromuscular junction and in the heart, and
it is often suggested that antibodies to some CNS channels could
be associated with CNS disease. It can also be argued that a
mechanism of similar nature to CHB could be at play in autism,
where maternal autoantibodies could be affecting calcium channels
and thus dysregulating ionic currents in neurons, glial or endothelial
cells that line brain vessels.

Recent evidence has shown that antibodies directed against angiotensin
II type I receptors are also highly associated with
preeclampsia. It has been suggested that maternal
antibodies could activate these receptors and subsequently plasma
calcium channels, leading to an increase in intracellular calcium
levels and to downstream activation of calcium signaling pathways
[15381659,
12593997].

Plasma serotonin levels in mothers of ASD subjects was observed
in one study to be significantly lower than in control mothers.
Low maternal serotonin levels were proposed
to be a risk factor for autism through effects on fetal brain
development, especially in the light of a recent murine study
showing that maternally-derived serotonin, as opposed to fetus-derived,
is crucial for murine embryonic development [6939857,
17182745].
Worth noting is that lowered serotonin levels are a frequent
feature of viral infections, since maternal
viral infection and/or reactivation is a proposed risk factor
in etiology of autism [16842443,
2771632,
9026369].

The mechanism behind the effects of serotonin on brain development
and function is hypothesised to be at least in part linked to
the inhibitory effects of serotonin on voltage-gated calcium
currents, most likely through activation of its 5-HT1A and possibly
5-HT2A receptors [11494406,
8118677,
11976386].
The importance of serotonin in promoting directed neuronal migration
is hypothesised to be due to its G-protein-dependent modulation
of voltage-gated calcium channels in the migrating cell [12401168].
Of interest here is that 5-HT1A agonists, in additon to reducing
ischemic brain injury in vitro, have been proposed as possible
agents for prevention of (virally-induced) neuro-psychiatric
disorders (see AIDS ref above, also Infectious_Agents).

In the context of prenatal/maternal infection as a possible
risk factor, worth noting is the greater occurrence of placental
trophoblast inclusions observed recently in ASD individuals
compared to controls [16806106],
since infectious agents have been observed
to persist and replicate in placental trophoblast cells, often
causing their inclusions [2446593,
11743054,
6283965,
3918685].
In additon, human placental trophoblasts express voltage gated
calcium channels, and their activation induces secretion of
corticotropim releasing hormone (CRH), thought
to be closely linked to acute or chronic metabolic,
psychological, physical or infectious stress during
pregnancy. CRH hypersecretion has been associated to depression
and anxiety-related disorders, anorexia nervosa and neurodegenerative
diseases [10999834,
17127316].
For example it has been shown that exposure of animals to stressful
experience (restrain stress) during pregnancy can exert effects
on calcium ion channels of offspring hippocampal neurons and
that such calcium channel disturbances may play a role in prenatal
stress-induced neuronal loss and oxidative damage in offspring
brain [17123551].

Thyroid function as a risk factor and involvement of calcium signalling

Familial autoimmune thyroid disease has recently been identified
as a risk factor for regression in children with ASD and hypothyroid
hormone deficiency in early development has been proposed to
cause central nervous system damage that could lead to emergence
of autistic symptoms [16598435,
1577897].

Thyroid hormone is essential for the development and maturation
of the CNS in mammals. Deficency of the hormone during development
negatively affects performance in tasks of learning and memory
in rodents, and was shown to cause abnormalities of the CNS
such as incomplete maturation of neurons and glial cells, reduction
in synaptic densities and myeling deficits. Rodent with mild
and transient neonatal hypothyroidism has been proposed as a
novel model for autism.

It has been speculated that behavioral deficits associated with
developmental hypothyroidism are due to enhanced calcium
influx through LTCC [15673845]
and/or impairments of the calcium ATPase activity during critical
stages of brain development [16293371].
Amongst other things thyroid hormone regulates neurotransmitter
release in neonatal rat hippocampus and hypothyroid
rats exhibit an increase in the calcium-dependent neurotransmitter
secretion (see Neurotransmitters),
an effect that could be reversed by administering thyroid hormone
[11882369].
In additon, a recent study demonstrated that thyroid hormone
insufficiency during early postnatal period permanently alters
expression of calcium binding protein parvalbumin (PV) in GABAerigic
interneurons and compromises their inhibitory function [17008398].

In cardiac tissue, hypothyroidism impairs the early
postnatal maturation of voltage gated calcium channels as regards
both their distribution and mRNA expression. L-type and T-type
calcium channels, as well as the ryanodine channel are amongst those affected
by actions of thyroid hormone. Hyperthyroidism is associated
with increases in cardiac LTCC currents, and changes in thyroid
status markedly influence cardiac contractile and electrical
activity. These mechanism are thought to be the likely causes
of development of heart failure in hyperthyroidism [9539869,
16238192,
12914768,
10710339]